DESCRIPTION

Acetylcysteine is the nonproprietary name for the N-acetyl derivative of the naturally occurring amino acid, L-cysteine. Chemically, it is N-acetyl-L-cysteine.

The compound is a white crystalline powder which melts in the range of 104°
to 110°C and has a very slight odor. The structural formula of acetylcysteine
is:

C5H9NO3 .............. M.W.=163.19

Acetylcysteine Solution (n-acetyl-l-cysteine) , USP is supplied as a sterile unpreserved solution (not for injection) in vials containing a 10% (100 mg/mL) or 20% (200 mg/mL) solution of acetylcysteine as the sodium salt. The inactive ingredients are edetate disodium, sodium hydroxide and Sterile Water for Injection, USP. The pH of the solution ranges from 6.0 to 7.5. It is administered by inhalation or direct instillation for mucolysis, or orally for acetaminophen overdosage.

Acetylcysteine, administered orally, is indicated as an antidote to prevent
or lessen hepaticinjury which may occur following the ingestion of a potentially
hepatotoxic quantity of acetaminophen. It is essential to initiate treatment
as soon as possible after the overdose and, in any case, within 24 hours of
ingestion.

DOSAGE AND ADMINISTRATION

ACETYLCYSTEINE AS A MUCOLYTIC AGENT

General

Acetylcysteine Solution, USP (n-acetyl-l-cysteine) is available in rubber stoppered glass vials containing
10 mL or 30 mL. The 20% solution may be diluted to a lesser concentration with
either SodiumChloride Injection, Sodium Chloride for Inhalation, Sterile Water
for Injection, or Sterile Water for Inhalation. The 10% solution may be used
undiluted.

Acetylcysteine does not contain an antimicrobial agent, and care must be taken
to minimize contamination of the sterile solution. If only a portion of the
solution in a vial is used, store the remainder in a refrigerator and use for
inhalation only within 96 hours.

Nebulization- Face Mask, Mouthpiece, Tracheostomy: When nebulized
into a face mask, mouthpiece, or tracheostomy, 1 to 10 mL of the 20% solution
or 2 to 20 mL of the 10% solution may be given every 2 to 6 hours; the recommended
dose for most patients is 3 to 5 mL of the 20% solution or 6 to 10 mL of the
10% solution three to four times a day.

Nebulization - Tent, Croupette: In special circumstances it may be necessary
to nebulize into a tent or Croupette, and this method of use must be individualized
to take into account the available equipment and the patient's particular needs.
This form of administration requires very large volumes of the solution, occasionally
as much as 300 mL during a single treatment period.

If a tent or Croupette must be used, the recommended dose is the volume of
acetylcysteine (using 10 or 20%) that will maintain a very heavy mist in the
tent or Croupette for the desired period. Administration for intermittent or
continuous prolonged periods, including overnight, may be desirable.

Direct Instillation: When used by direct instillation, 1 to 2 mL of
a 10% to 20% solution may be given as often as every hour.

When used for the routine nursing care of patients with tracheostomy, 1 to
2 mL of a 10% to 20% solution may be given every 1 to 4 hours by instillation
into the tracheostomy.

Acetylcysteine may be introduced directly into a particular segment of the
bronchopulmonary tree by inserting (under local anesthesia and direct vision)
a small plastic catheter into the trachea. Two to 5 mL of the 20% solution may
then be instilled by means of a syringe connected to the catheter.

Acetylcysteine may also be given through a percutaneous intratracheal catheter.
One to 2 mL of the 20% or 2 to 4 mL of the 10% solution every 1 to 4 hours may
then be given by a syringe attached to the catheter.

Diagnostic Bronchograms: For diagnostic bronchial studies, 2 or 3 administrations
of 1 to 2 mL of the 20% solution or 2 to 4 mL of the 10% solution should be
given by nebulization or by instillation intratracheally, prior to the procedure.

Administration of Aerosol

Materials: Acetylcysteine solution (n-acetyl-l-cysteine) may be administered using conventional
nebulizers made of plastic or glass. Certain materials used in nebulization
equipment react with acetylcysteine. The most reactive of these are certain
metals (notably iron and copper) and rubber. Where materials may come into contact
with acetylcysteine solution (n-acetyl-l-cysteine) , parts made of the following acceptable materials
should be used: glass, plastic, aluminum, anodized aluminum, chromed metal,
tantalum, sterling silver, or stainless steel. Silver may become tarnished after
exposure, but this is not harmful to the drug action or to the patient.

Nebulizing Gases: Compressed tank gas (air) or an air compressor should
be used to provide pressure for nebulizing the solution. Oxygen may also be
used but should be used with usual precautions in patients with severe respiratory
disease and CO2 retention.

Apparatus: Acetylcysteine solution (n-acetyl-l-cysteine) is usually administered as fine nebulae
and the nebulizer used should be capable of providing optimal quantities of
a suitable range of particle sizes.

Commercially available nebulizers will produce nebulae of acetylcysteine satisfactory
for retention in the respiratory tract. Most of the nebulizers tested will supply
a high proportion of the drug solution as particles of less than 10 microns
in diameter. Mitchell2 has shown that particles less than 10 microns should
be retained in the respiratory tract satisfactorily.

The nebulized solution may be inhaled directly from the nebulizer. Nebulizers may also be attached to plastic face masks or plastic mouthpieces. Suitable nebulizers may also be fitted for use with the various intermittent positive pressure breathing (IPPB) machines. The nebulizing equipment should be cleaned immediately after use because the residues may clog the smaller orifices or corrode metal parts.

Hand bulbs are not recommended for routine use for nebulizing acetylcysteine because their output is generally too small. Also, some hand-operated nebulizers deliver particles that are larger than optimum for inhalation therapy.

Acetylcysteine solution (n-acetyl-l-cysteine) should not be placed directly into the chamber of
a heated (hot pot) nebulizer. A heated nebulizer may be part of the nebulization
assembly to provide a warm saturated atmosphere if the acetylcysteine aerosol
is introduced by means of a separate unheated nebulizer. Usual precautions for
administration of warm saturated nebulae should be observed.

The nebulized solution may be breathed directly from the nebulizer. Nebulizers
may also be attached to plastic face masks, plastic face tents, plastic mouthpieces,
conventional plastic oxygen tents, or head tents. Suitable nebulizers may also
be fitted for use with the various intermittent positive pressure breathing
(IPPB) machines.

The nebulizing equipment should be cleaned immediately after use, otherwise
the residues may occlude the fine orifices or corrode metal parts.

Prolonged Nebulization: When three-fourths of the initial volume of
acetylcysteine solution (n-acetyl-l-cysteine) has been nebulized, a quantity of Sterile Water for
Injection, USP (approximately equal to the volume of solution remaining) should
be added to the nebulizer. This obviates any concentration of the agent in the
residual solvent remaining after prolonged nebulization.

Compatibility: The physical and chemical compatibility of acetylcysteine
solutions with certain other drugs that might be concomitantly administered
by nebulization, direct instillation, or topical application, has been studied.

Acetylcysteine should not be mixed with certain antibiotics. For example, the
antibiotics tetracycline hydrochloride, oxytetracycline hydrochloride and erythromycin
lactobionate were found to be incompatible when mixed in the same solution.
These agents may be administered from separate solutions if administration of
these agents is desirable.

The supplying of these data should not be interpreted as a recommendation for
combining acetylcysteine with other drugs. The table is not presented as positive
assurance that no incompatibility will be present, since these data are based
only on short-term compatibility studies done in the Mead Johnson Research Center.mManufacturers
may change their formulations, and this could alter compatibilities. These data
are intended to serve only as a guide for predicting compounding problems.

If it is deemed advisable to prepare an admixture, it should be administered
as soon as possible after preparation. Do not store unused mixtures.

ACETYLCYSTEINE AS AN ANTIDOTE FOR ACETAMINOPHEN OVERDOSAGE

General

Regardless of the quantity of acetaminophen reported to have been ingested, administer acetylcysteine immediately if 24 hours or less have elapsed from the reported time of ingestion of an overdose of acetaminophen. Do not await results of assays for acetaminophen level before initiating treatment with acetylcysteine solution (n-acetyl-l-cysteine) . The following procedures are recommended:

The stomach should be emptied promptly by lavage or by inducing emesis
with syrup of ipecac. Syrup of ipecac should be given in a dose of 15 mL for
children up to age 12 and 30 mL for adolescents and adults followed immediately
by drinking copious quantities of water. The dose should be repeated if emesis
does not occur in 20 minutes.

In the case of a mixed drug overdose, activated charcoal may be indicated.
However, if activated charcoal has been administered, lavage before administering
acetylcysteine treatment. Activated charcoal adsorbs acetylcysteine in
vitro and may do so in patients and thereby may reduce its effectiveness.

Administer the loading dose of acetylcysteine, 140 mg per kg of body weight.
(Prepare acetylcysteine for oral administration as described in the specific
Dosage Guide and Preparation table.)

Determine the subsequent action based on predetoxification plasma acetaminophen
information. Choose ONE of the following four courses of therapy.

Predetoxification plasma acetaminophen level is clearly in toxic range
(See Acetaminophen Assays - Interpolation and Methodology below):
Administer a first maintenance dose (70 mg/kg acetylcysteine) 4 hours
after the loading dose. The maintenance dose is then repeated at 4-hour
intervals for a total of 17 doses. Monitor hepatic and renal function
and electrolytes throughout the detoxification process.

Predetoxification acetominophen level could not be obtained:
Proceed as in A.

Predetoxification acetominophen level is clearly in the nontoxic range
(beneath the dashed line on the nomogram) and you know that acetominophen
overdose occurred at least 4 hours before the predetoxification acetaminophen
plasma assays:
Discontinue administration of acetylcysteine.

Predetoxification acetominophen level was in the nontoxic range, but
time of ingestion was unknown or less than 4 hours.
Because the level of acetaminophen at the time of the predetoxification
assay may not be a peak value (peak may not be achieved before 4 hours
post-ingestion), obtain a second plasma level in order to decide wether
or not the full 17-dose detoxification treatment is necessary.

If the patient vomits any oral dose within 1 hour of administration, repeat
that dose.

In the occasional instances where the patient is persistently unable to
retain the orally administered acetylcysteine, the antidote may be administered
by duodenalintubation.

Preparation of Acetylcysteine Solution (n-acetyl-l-cysteine) for Oral Administration: Oral
administration requires dilution of the 20% solution with diet cola, or other
diet soft drinks, to a final concentration of 5% (See Dosage Guide and Preparation
table). If administered via gastric tube or Miller-Abbott tube, water may
be used as the diluent. The dilutions should be freshly prepared and utilized
within one hour. Remaining undiluted solutions in opened vials can be stored
in the refrigerator up to 96 hours. ACETYLCYSTEINE SOLUTION (n-acetyl-l-cysteine) IS NOT APPROVED
FOR PARENTERAL INJECTION.

Acetaminophen Assays - Interpretation and Methodology: The acute ingestion
of acetaminophen in quantities of 150 mg/kg or greater may result in hepatic
toxicity. However, the reported history of the quantity of a drug ingested as
an overdose is often inaccurate and is not a reliable guide to therapy of the
overdose.

THEREFORE, PLASMA OR SERUM ACETAMINOPHEN CONCENTRATIONS, DETERMINED AS EARLY
AS POSSIBLE, BUT NO SOONER THAN FOUR HOURS FOLLOWING AN ACUTE OVERDOSE, ARE
ESSENTIAL IN ASSESSING THE POTENTIAL RISK OF HEPATOTOXICITY. IF AN ASSAY FOR
ACETAMINOPHEN CANNOT BE OBTAINED, IT IS NECESSARY TO ASSUME THAT THE OVERDOSE
IS POTENTIALLY TOXIC.

Interpretation of Acetaminophen Assays

When results of the plasma acetaminophen assay are available refer to the
nomogram below to determine if plasma concentration is in the potentially
toxic range. Values above the solid line connecting 200 mcg/mL at 4 hours
with 50 mcg/mL at 12 hours are associated with a possibility of hepatic toxicity
if an antidote is not administered. (Do not wait for assay results to begin
acetylcysteine treatment.)

If the predetoxification plasma level is above the broken line, continue
with maintenance doses of acetylcysteine. It is better to err on the safe
side and thus the broken line is placed 25% below the solid line which defines
possible toxicity.

If the predetoxification plasma level is below the broken line described
above, there is minimal risk of hepatic toxicity and acetylcysteine treatment
can be discontinued.

*If patient weighs less than 20 kg (usually patients younger
than 6 years), calculate the dose of acetylcysteine. Each mL of 20% acetylcysteine
solution contains 200 mg of acetylcysteine. The loading dose is 140 mg per
kilogram of body weight. The maintenance dose is 70 mg/kg. Three (3) mL
of diluent are added to each mL of 20% acetylcysteine solution. Do not decrease
the proportion of diluent.

Estimating Potential for Hepatotoxicity

The following nomogram has been developed to estimate the probability that plasma levels in relation to intervals post-ingestion will result in hepatotoxicity.

HOW SUPPLIED

Acetylcysteine Solution, USP (n-acetyl-l-cysteine) , is available in rubber stopped glass vials containing
10 or 30 mL. The 20% solution may be diluted to a lesser concentration with
either Sodium Chloride for Injection, Sodium Chloride for Inhalation, Sterile
Water for Injection, or Sterile Water for Inhalation. The 10% solution may be
used undiluted.

Acetycysteine is sterile, not for injection and can be used for inhalation
(mucolytic agent) or oral administration (acetaminophen antidote). It is available
as follows:

Acetylcysteine Solution, USP (n-acetyl-l-cysteine) does not contain an antimicrobial agent, and care
must be taken to minimize contamination of the sterile solution. Dilutions of
acetylcysteine should be used freshly prepared and utilized within one hour.
If only a portion of the solution in a vial is used, store the remaining undiluted
portion in a refrigerator and use within 96 hours.

Acquired sensitization to acetylcysteine has been reported rarely. Reports
of sensitization in patients have not been confirmed by patch testing. Sensitization
has been confirmed in several inhalation therapists who reported a history of
dermal eruptions after frequent and extended exposure to acetylcysteine.

Reports of irritation to the tracheal and bronchial tracts have been received
and although hemoptysis has occurred in patients receiving acetylcysteine such
findings are not uncommon in patients with bronchopulmonary disease and a causal
relationship has not been established.

ACETYLCYSTEINE AS AN ANTIDOTE FOR ACETAMINOPHEN OVERDOSAGE

Oral administration of acetylcysteine, especially in the large doses needed to treat acetaminophen overdose, may result in nausea, vomiting and other gastrointestinal symptoms. Rash with or without mild fever has been observed rarely.

DRUG INTERACTIONS

Drug stability and safety of acetylcysteine when mixed with other drugs in
a nebulizer have not been established.

Warnings & Precautions

WARNINGS

ACETYLCYSTEINE AS A MUCOLYTIC AGENT

After proper administration of acetylcysteine, an increased volume of liquefied
bronchial secretions may occur. When cough is inadequate, the airway must be
maintained open by mechanical suction if necessary. When there is a mechanical
block due to foreign body or local accumulation, the airway should be cleared
by endotracheal aspiration, with or without bronchoscopy. Asthmatics under treatment
with acetylcysteine should be watched carefully. Most patients with bronchospasm
are quickly relieved by the use of a bronchodilator given by nebulization. If
bronchospasm progresses, the medication should be discontinued immediately.

ACETYLCYSTEINE AS AN ANTIDOTE FOR ACETAMINOPHEN OVERDOSAGE

Generalized urticaria has been observed rarely in patients receiving oral acetylcysteine for acetaminophen overdose. If this occurs or other allergic symptoms appear, treatment with acetylcysteine should be discontinued unless it is deemed essential and the allergic symptoms can be otherwise controlled. If encephalopathy due to hepatic failure becomes evident, acetylcysteine treatment should be discontinued to avoid further administration of nitrogenous substances. There are no data indicating that acetylcysteine influences hepatic failure, but this remains a theoretical possibility.

PRECAUTIONS

ACETYLCYSTEINE AS A MUCOLYTIC AGENT

General

With the administration of acetylcysteine, the patient may observe initially
a slight disagreeable odor that is soon not noticeable. With a face mask there
may be stickiness on the face after nebulization. This is easily removed by
washing with water.

Under certain conditions, a color change may occur in acetylcysteine in the
opened bottle. The light purple color is the result of a chemical reaction which
does not significantly affect safety or mucolytic efficacy of acetylcysteine.

Continued nebulization of acetylcysteine solution (n-acetyl-l-cysteine) with a dry gas will result
in an increased concentration of the drug in the nebulizer because of evaporation
of the solvent. Extreme concentration may impede nebulization and efficient
delivery of the drug. Dilution of the nebulizing solution with appropriate amounts
of Sterile Water for Injection, USP, as concentration occurs, will obviate this
problem.

Carcinogenesis, Mutagenesis and Impairment of Fertility

Carcinogenesis: Carcinogenicity studies in laboratory animals have not
been performed with acetylcysteine alone, nor with acetylcysteine in combination
with isoproterenol.

Long-term oral studies of acetylcysteine alone in rats (12 months of treatment
followed by 6 months of observation) at doses up to 1,000 mg/kg/day (5.2 times
the human mucolytic dose) provided no evidence of oncogenic activity.

Mutagenesis: Published data1 indicate that acetylcysteine is not mutagenic
in the Ames test, both with and without metabolic activation.

Impairment of Fertility: A reproductive toxicity test to assess potential
impairment of fertility was performed with acetylcysteine (10%) combined with
isoproterenol (0.05%) and administered as an aerosol into a chamber of 12.43
cubic meters. The combination was administered for 25, 30, or 35 minutes twice
a day for 68 days before mating, to 200 male and 150 female rats; no adverse
effects were noted in dams or pups. Females after mating were continued on treatment
for the next 42 days.

Reproductive toxicity studies of acetylcysteine in the rat given oral doses
of acetylcysteine up to 1,000 mg/kg (5.2 times the human mucolytic dose) have
also been reported in the literature.1 The only adverse effect observed was
a slight non-dose-related reduction in fertility at dose levels of 500 or 1,000
mg/kg/day (2.6 or 5.2 times the human mucolytic dose) in the Segment I study.

Pregnancy: Teratogenic Effects: Pregnancy Category B

Teratology: In a teratology study of acetylcysteine in the rabbit, oral
doses of 500 mg/kg/day (2.6 times the human mucolytic dose) were administered
to pregnant does by intubation on days 6 through 16 of gestation. Acetylcysteine
was found to be nonteratogenic under the conditions of the study.

In the rabbit, two groups (one of 14 and one of 16 pregnant females) were exposed
to an aerosol of 10% acetylcysteine and 0.05% isoproterenol hydrochloride for
30 or 35 minutes twice a day from the 16th through the 18th day of pregnancy.
No teratogenic effects were observed among the offspring.

Teratology and a perinatal and postnatal toxicity study in rats were performed
with a combination of acetylcysteine and isoproterenol administered by the inhalation
route. In the rat, two groups of 25 pregnant females each were exposed to the
aerosol for 30 and 35 minutes, respectively, twice a day from the 6th through
the 15th day of gestation. No teratogenic effects were observed among the offspring.

In the pregnant rat (30 rats per group), twice-daily exposure to an aerosol
of acetylcysteine and isoproterenol for 30 or 35 minutes from the 15th day of
gestation through the 21st day postpartum was without adverse effect on dams
or newborns.

Reproduction studies of acetylcysteine with isoproterenol have been performed
in rats and of acetylcysteine alone in rabbits at doses up to 2.6 times the
human dose. These have revealed no evidence of impaired fertility or harm to
the fetus due to acetylcysteine. There are, however, no adequate and well-controlled
studies in pregnant women. Because animal reproduction studies may not always
be predictive of human responses, this drug should be used during pregnancy
only if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when acetylcysteine is administered to a nursing woman.

Overdosage & Contraindications

OVERDOSE

No information provided.

CONTRAINDICATIONS

ACETYLCYSTEINE AS A MUCOLYTIC AGENT

Acetylcysteine is contraindicated in those patients who are sensitive to it.

ACETYLCYSTEINE AS AN ANTIDOTE FOR ACETAMINOPHEN OVERDOSAGE

There are no contraindications to oral administration of acetylcysteine in the treatment of acetaminophen overdose.

Clinical Pharmacology

CLINICAL PHARMACOLOGY

ACETYLCYSTEINE AS A MUCOLYTIC AGENT

The viscosity of pulmonarymucous secretions depends on the concentrations
of mucoprotein and, to a lesser extent, deoxyribonucleic acid (DNA). The latter
increases with increasing purulence owing to the presence of cellular debris.
The mucolytic action of acetylcysteine is related to the sulfhydryl group in
the molecule. This group probably "opens" disulfide linkages in mucous thereby
lowering the viscosity. The mucolytic activity of acetylcysteine is unaltered
by the presence of DNA, and increases with increasing pH. Significant mucolysis
occurs between pH 7 and 9.

Acetylcysteine undergoes rapid deacetylation in vivoto yield cysteine
or oxidation to yield diacetylcysteine. Occasionally, patients exposed to the
inhalation of an acetylcysteine aerosol respond with the development of increased
airways obstruction of varying and unpredictable severity. Those patients who
are reactors cannot be identified a priori from a random patient population.
Even when patients are known to have reacted previously to the inhalation of
an acetylcysteine aerosol, they may not react during a subsequent treatment.
The converse is also true; patients who have had inhalation treatments of acetylcysteine
without incident may still react to a subsequent inhalation with increased airways
obstruction. Most patients with bronchospasm are quickly relieved by the use
of a bronchodilator given by nebulization. If bronchospasm progresses, the medication
should be discontinued immediately.

ACETYLCYSTEINE AS AN ANTIDOTE FOR ACETAMINOPHEN OVERDOSAGE

(Antidotal) Acetaminophen is rapidly absorbed from the upper gastrointestinal
tract with peak plasma levels occurring between 30 and 60 minutes after therapeutic
doses and usually within 4 hours following an overdose. The parent compound,
which is nontoxic, is extensively metabolized in the liver to form principally
the sulfate and glucuronide conjugates which are also nontoxic and are rapidly
excreted in the urine. A small fraction of an ingested dose is metabolized in
the liver by the cytochrome P-450 mixed function oxidase enzyme system to form
a reactive, potentially toxic, intermediate metabolite which preferentially
conjugates with hepatic glutathione to form the nontoxic cysteine and mercapturic
acid derivatives which are then excreted by the kidney. Therapeutic doses of
acetaminophen do not saturate the glucuronide and sulfate conjugation pathways
and do not result in the formation of sufficient reactive metabolite to deplete
glutathione stores. However, following ingestion of a large overdose (150 mg/kg
or greater) the glucuronide and sulfate conjugation pathways are saturated resulting
in a larger fraction of the drug being metabolized via the P-450 pathway. The
increased formation of reactive metabolite may deplete the hepatic stores of
glutathione with subsequent binding of the metabolite to protein molecules within
the hepatocyte resulting in cellular necrosis. Acetylcysteine has been shown
to reduce the extent of liver injury following acetaminophen overdose. Its effectiveness
depends on early oral administration, with benefit seen principally in patients
treated within 16 hours of the overdose. Acetylcysteine probably protects the
liver by maintaining or restoring the glutathione levels, or by acting as an
alternate substrate for conjugation with, and thus detoxification of, the reactive
metabolite.